The 5-HT1A receptor is implicated in the pathology of anxiety, major depression and suicide. Studies with mutant mice indicate that the 5-HT1A receptor is necessary for the long-term viability of brain networks. Preliminary studies suggest that the activation of signaling molecules downstream of the 5-HT1A receptor is attenuated in the occipital cortex (OC) of suicides. We will determine whether this attenuation of signal transduction pathways is a characteristic of major depression or related to the diathesis for suicide by comparing suicides with major depression (MDD) to suicides with schizophrenia (SZ) and to nonpsychiatric, nonsuicide controls. We will evaluate four brain regions, one where we have found changes in both major depression and suicide (ventral prefrontal cortex, vPFC) and three regions where the findings seem more specifically linked to major depression (anterior cingulate cortex [ACC], dorsolateral PFC [BA9] and hippocampus). We predict signal transduction effects related to suicide will be present in both suicide groups and confined to the vPFC. We would predict the signal transduction changes related to MDD will be found in the MDD suicide group and not the other two groups and in the ACC and dorsal prefrontal cortex. We will test the hypothesis that 5-HT1A receptor-activated transduction pathways linked to cell survival are downregulated in specific brain regions relevant to major depression or for suicide. We will measure signaling proteins downstream of 5-HT1A receptors that are regulated via coupling to Gi/o and Gsubunits. One pathway involves the Gai-mediated inhibition of adenylyl cyclase (AC) and protein kinase A (PKA). The 5-HT-dependent inhibition of AC is normally counterbalanced by the concomitant activation of cell survival pathways. We propose that the reduced inhibition of AC in suicides represents a mechanism to counteract the reduction in the activity of the transduction pathways activated via the Gbg subunit. Investigating 5-HT1A receptor activation of NFkB, PI3-K/Akt and ERKs in suicide will advance our understanding of the role of 5-HT1A receptor signal pathways in depression and suicidal behavior. The cerebellar hemisphere will serve as a control region. We will also measure neuronal density, the levels of pro-apoptotic signaling molecules and death effectors. We hypothesize that the viability or functionality of brain cells that express 5-HT1A receptors is neuroendangered in major depression or suicide. Unraveling these events biochemically will yield crucial insights into the neurobiology of depression and suicide, major mental health problems in the US and the world. It may also identify novel drug targets for the treatment of depression and for the prevention of suicide. PUBLIC HEALTH RELEVANCE: Suicidal behavior is a major health problem in the United States and the world. With 30,000 deaths by suicide per year in the US, suicide is the 11th leading cause of death. We have data indicating that the neuroprotective cellular pathways associated with the serotonin 1A receptor are altered in suicide. We want to explore this further by studying these pathways in various brain regions of suicides (depressed and schizophrenic) and normal controls. We hope to gain insight into the neurobiology of suicide versus depression and identify novel drug targets for treatment of depression and prevention of suicide.